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Potassium channels keep popping up as an area to watch lately...



Potassium channels K(v)1.3 and K(v)1.5 are expressed on blood-derived dendritic cells in the central nervous system.

Ann Neurol. 2006 May 25;
Mullen KM, Rozycka M, Rus H, Hu L, Cudrici C, Zafranskaia E, Pennington MW, Johns DC, Judge SI, Calabresi PA.
Department of Neurology, Johns Hopkins University, Baltimore, MD.

OBJECTIVE: Potassium (K(+)) channels on immune cells have gained attention recently as promising targets of therapy for immune-mediated neurological diseases such as multiple sclerosis (MS). We examined K(+) channels on dendritic cells (DCs), which infiltrate the brain in MS and may impact disease course.

METHODS: We identified K(+) channels on blood-derived DCs by whole-cell patch-clamp analysis, confirmed by immunofluorescent staining. We also stained K(+) channels in brain sections from MS patients and control subjects. To test functionality, we blocked K(v)1.3 and K(v)1.5 in stimulated DCs with pharmacological blockers or with an inducible dominant-negative K(v)1.x adenovirus construct and analyzed changes in costimulatory molecule upregulation.

RESULTS: Electrophysiological analysis of DCs showed an inward-rectifying K(+) current early after stimulation, replaced by a mix of voltage-gated K(v)1.3- and K(v)1.5-like channels at later stages of maturation. K(v)1.3 and K(v)1.5 were also highly expressed on DCs infiltrating MS brain tissue. Of note, we found that CD83, CD80, CD86, CD40, and interleukin-12 upregulation were significantly impaired on K(v)1.3 and K(v)1.5 blockade.

INTERPRETATION: These data support a functional role of K(v)1.5 and K(v)1.3 on activated human DCs and further define the mechanisms by which K(+) channel blockade may act to suppress immune-mediated neurological diseases.

http://www.ncbi.nlm.nih.gov/entrez/quer ... med_docsum

Dignan--

Potassium channels keep popping up as an area to watch lately...

Indeed they do and I'd like to suggest the Hopkins researchers consider a clinical trial of progesterone as a potassium channel inhibitor, especially if they insist on pursuing MS as an "auto-immune" disease .

From the abstract you posted:

These data support a functional role of K(v)1.5 and K(v)1.3 on activated human DCs and further define the mechanisms by which K(+) channel blockade may act to suppress immune-mediated neurological diseases.

Another abstract Potassium Channels In MS notes:

To date, only 2 broad-spectrum K(+) channel blockers, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP), have been tested in MS patients. Although both 4-AP and 3,4-DAP produce clear neurologic benefits, their use has been limited by toxicity.

It's very unfortunate IMO the researchers don't seem to have any awareness that progesterone also appears to be a potassium channel blocker. One would hope it also wouldn't have as many problems with toxicity. Based on the info in the following abstract and since pregnant women seem to have fewer relapses in the third trimester of pregnancy when progesterone levels are high, it seems to me progesterone might be a good candidate for a clinical trial aimed at "inhibiting K+ channels".

A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes

Progesterone effectively blocked a broad spectrum of K+ channels, reducing both Kv1.3 and charybdotoxin-resistant components of KV current and KCa current in T cells, as well as blocking several cloned KV channels expressed in cell lines.

We propose that direct inhibition of K+ channels in T cells by progesterone contributes to progesterone-induced immunosuppression.

I'm amazed no one seems to have "connected" these dots so far. Or, maybe they have and there's a reason to ignore progesterone. I have to wonder though.

Take care everyone--I'm still optimistic about the potential of hormones.

Sharon

I posted this link on another topic already, but check out this company.

www.acorda.com

Thay have a trial going on right now that is focused on blocking leaking potassium channels to restore function to damaged nerves in MS patients. I pray that it is a breakthrough of sorts.

G